Small-molecule modulation of Ras signaling
Cet article passe en revue les travaux récents sur de petites molécules ouvrant la voie au développement de thérapies ciblant les protéines Ras
Despite intense efforts in pharmaceutical industry and academia, a therapeutic grip on oncogenic Ras proteins has remained elusive. Mutated Ras is associated with ∼20−30% of all human cancers often not responsive to established therapies. In particular, K-Ras, the most frequently mutated Ras isoform, is considered one of the most important but 'undruggable' targets in cancer research. Recently, new cavities on Ras for small-molecule ligands were identified, and selective direct targeting of mutated K-RasG12C has become possible for what is to our knowledge the first time. In addition, impairment of Ras spatial organization, in particular via targeting the prenyl-binding Ras chaperone PDEδ, has opened a fresh perspective in anticancer research. These recent advances fuel hopes for the development of new drugs targeting Ras.